Phenotypic variability in a family with a mitochondrial DNA T8993C mutation

Two patients are described in a family with a mitochondrial DNA T8993C point mutation. Patient 1, the proband, was a 4-year-old male, and his clinical features were consistent with those of Leigh syndrome, including lactic acidosis, motor development delay, and symmetric basal ganglia lesions on magnetic resonance imaging (MRI). His mental development was delayed mildly, but he has not demonstrated neurologic deterioration. Patient 2 was his maternal aunt. She developed her first neurologic sign at 18 months of age, thereafter her development ceased and regressed. She had lost her head control and become bedridden by 4 years of age and died at 20 years of age, demonstrating a more severe clinical course than that of Patient 1. Analysis of mitochondrial DNA from peripheral leukocytes of Patient 1 revealed a T8993C mutation of 99%. Patient 2 was demonstrated to have the same mutation at high abundance (99%) in the frozen myocardium and in the formaldehyde preserved spinal cord, with only 18% mutant mitochondrial DNA present in the formaldehyde preserved sciatic nerve. The mother of Patient 1, who was phenotypically normal (sister of Patient 2), had 35% mutant mitochondrial DNA in peripheral leukocytes. The authors' findings suggest that T8993C phenotypes are highly variable and that the proportion of the mutant mitochondrial DNA may vary among tissues and not correlate well with clinical severity.